Identification of circulating inflammation cytokines as a mediator of gut microbiota and type 2 diabetes mellitus: a Mendelian randomization study

Abstract

Background: Several studies have suggested that the gut microbiota (GM) may be associated with type 2 diabetes mellitus (T2DM). However, the causal relationship between GM and T2DM and whether inflammatory cytokines act as mediators remain unclear.

Aims: To investigate the association between GM and T2DM and the proportion of this association that is mediated through inflammatory cytokines.

Methods: We conducted a bidirectional and mediation Mendelian randomization (MR) study utilizing data from the genome-wide association studies (GWAS) of four sources of GM taxa (MiBioGen consortium, n = 18,340; Dutch Microbiome Project, n = 7,738; German biobanks, n = 8,956; FINRISK 2002, n = 5,959), a meta-analysis of inflammatory proteins (n = 14,824), and European-ancestry T2DM (n = 1,528,967). The inverse variance weighted method was applied as the primary method. And two-step MR was employed to identify potential mediating inflammatory cytokines.

Results: We found evidence for 28 positive and 20 negative causal effects between multiple sources of GM and T2DM using at least two MR methods. And there were 2 positive and 5 negative causal relationships between cytokines and T2DM using at least two MR methods. The mediation MR analysis found that interferon-gamma (IFN-γ) mediated the causal effects of species Kandleria vitulina on T2DM (proportion mediated = 22.5%, P = 0.022).

Conclusion: The MR study supports the causal effect between Kandleria vitulina species and T2DM, with a potential mediating role played by inflammatory factor IFN-γ. Such result would serve as evidence for GM-targeted and cytokine-targeted therapy to prevent T2DM.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13098-025-01792-8.

Keywords: Causal inference; Gut microbiota; Inflammatory; Mendelian randomization study; Type 2 diabetes mellitus.

Fig. 1

Study design and flow chart. Step 1 represents the bi-directional causal effects between GM and T2DM. Step 2 represents the bi-directional causal effects between inflammation cytokines and T2DM. Step 3 represents two-step MR analysis of the effect of GM on T2DM via the mediator inflammatory cytokines: ‘β1’ reflects the causal effect of GM on cytokines; ‘β2’ indicated the causal effect of cytokines on T2DM; ‘β3’ was the total effect of GM on T2DM. GM, Gut microbiota; T2DM, type 2 diabetes mellitus; MR, mendelian randomization; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; MVMR, multivariable MR

Fig. 2

Mendelian randomization results of causal effects between 211 taxonomies from MiBioGen consortium and T2DM

Fig. 3

Mendelian randomization results of causal effects between 207 taxonomies from Dutch Microbiome Project and T2DM

Fig. 4

Mendelian randomization results of causal effects between 430 taxonomies from German biobanks and T2DM

Fig. 5

Mendelian randomization results of causal effects between 471 taxonomies from FR02 and T2DM

Fig. 6

Heatmap showing causality of 91 inflammatory cytokines on T2DM